1. Field of the Invention
The present invention relates to methods for treating a dermatologic syndrome known as hand-foot syndrome, or palmar-plantar erythrodysesthesia syndrome (PPES), which can be caused by chemotherapeutic regimens that utilize drugs such as capecitabine, 5-fluorouracil ("fluorouracil"), cytarabine, or doxorubicin.
2. Description of Related Art
Chemotherapeutic regimens that utilize drugs such as capecitabine, fluorouracil, cytarabine, and doxorubicin have been shown to cause a dermatologic syndrome known as hand-foot syndrome, or palmar-plantar erythrodysesthesia syndrome (PPES). [Comandone, et al., Anticancer Res. 13:1781 (1993); Fabian, et al., Investigational New Drugs 8:57 (1990); Gordon et al., Cancer. 75:2169 (1995); Lokich, et al., Ann. Intern. Med 101:798 (1984); Vogelzang, et al., Ann. Intern. Med. 103:303 (1985)]. PPES initially starts with dysesthesia (an abnormal feeling of discomfort with weight bearing or touch) in the hands and feet, followed by edema and erythema, and ultimately, fissuring and ulceration involving the fingers, toes, palms and plantar aspects of the feet. As the syndrome progresses, the patient may experience extreme pain when grasping objects or walking. Histologically the condition is marked by a thickened granular layer, marked hyperkeratosis with parakeratosis, and many apoptotic keratinocytes. Unlike many other inflammatory dematoses, the apoptotic cells are not associated with local lymphocytes. There may also be focal basilar vacuolization and a perivascular lymphocytic infiltrate, along with melanin incontinence in the papillary dermis. [See Gordon, et al., Cancer 75:2169, 2172 (1995). PPES may also affect areas of the body other than the hands and feet, for example areas of the skin to which pressure is applied, such as at the belt or bra line. The severity of PPES may be graded on a 0-3 scale. A grade of 0 indicates no PPES; grade 1 indicates mild PPES; grade 2 indicates moderate PPES; and grade 3 indicates severe PPES. [Fabian, et al., Investigational New Drugs 8:57 (1990)].
Doxorubicin, an anthracycline, is commonly administered for a wide range of solid tumors and hematologic malignancies. Liposomal doxorubicin preparations, which are made of small particles of doxorubicin encapsulated in hydrophilic lipid particle bilayers, have been investigated as safer and potentially more active alternatives to the parent compound. Polyethyleneglycol (PEG) coated liposome technology greatly alters the pharmacokinetics of doxorubicin with the PEG coating, resulting in major differences in doxorubicin clearance and distribution, along with significant increases in drug concentrations in tumors. Pegylated (PEG-coated) liposomal doxorubicin has proven effective in the treatment of AIDS-related Kaposi's sarcoma, ovarian cancer refractory to platinum and paclitaxel therapies, and metastatic breast cancer.
The incidence of severe PPES, as a result of pegylated liposomal doxorubicin therapy has been reported to be between 3.4% and 34%, depending on drug dose and schedule. [James, et al., Clin. Oncol. 6:294 (1994); Muggia, et al., J. Clin. Oncol. 15:987(1997); Northfelt, et al., J. Clin. Pharmacol. 36:55 (1996); Simpson et al., Clin. Oncol. 5:372 (1993); Uziely et al., J. Clin. Oncol. 13:1777 (1995)]. Although PPES is noted also to occur with prolonged administrations of other chemotherapeutic regimes, whether these drugs have a common mechanism for causing the syndrome is not known. [Comandone, et al., Anticancer Res. 13:1781 (1993); Fabian, et al., Investigational New Drugs 8:57 (1990); Gordon, et al., Cancer 75:2169 (1995); Leichman, et al., J. Natl. Cancer Inst. 85:41 (1993); Levine, et al., Arch. Dermatol. 121:102 (1985); Lokich, et al., Ann. Intern. Med 101:798 (1984); Lokich, et al., J. Clin. Oncol. 7:425 (1989); Vogelzang, et al., Ann. Intern. Med 103:303 (1985)].
Tissue extravasation reactions sometimes occur when chemotherapeutic agents inadvertently leak out of a blood vessel into which the drug is introduced, and into the surrounding tissue. Such reactions can cause severe injury to the surrounding tissue, often requiring plastic surgery, such as skin grafting, to repair the damaged tissue. This type of injury differs from PPES in that an extravasation reaction is a local injury caused by direct contact between a particular drug and affected tissue. PPES, on the other hand is a systemic reaction caused by a drug that is circulating in the bloodstream. PPES primarily affects the hands and feet of a patient, not the vicinity of the site at which the drugs are intravenously introduced into the patient.
Topical 99% (by weight, with 1% water) dimethyl sulfoxide (DMSO) has shown strong activity in treating tissue extravasation reactions that occur during intravenous administration of doxorubicin. [Bertelli et al., J. Clin. Oncol. 13:2851 (1995); Olver et al., J. Clin. Oncol. 6:1732 (1988)]. In a clinical study by Olver et al., 20 consecutive patients were treated with topical 99% DMSO for anthracycline soft tissue extravasation. Use of the 99% formulation four times daily for up to 14 days was shown to reduce doxorubicin soft tissue damage. At three months post DMSO treatment, 38% of the patients had no sign of residual damage and in 63% of the patients, only a pigmented, indurated skin lesion remained, without any sign of ulceration. Because no patients progressed to ulceration, the investigators documented a true ulceration range of 0-17% (95% confidence interval) compared to the 30% progression rate to ulceration observed by Larson [Cancer 49:1796 (1982)] when only ice was applied to the extravasation site. More recently, Bertelli et al. [J. Clin. Oncol. 13:2851] reported complete recovery from doxorubicin extravasation injury in 11 of 11 patients treated three times daily with 99% topical DMSO. DMSO is known to be rapidly absorbed through intact skin and mucous membranes. Additionally, DMSO has been reported to exert anti-inflammatory action, locoregional analgesic, and histamine-like vasodilatory effects. [David, Ann. Rev. Pharmacology, 12:353 (1972)].
Current methods for treating PPES include dose reduction, lengthening of the drug administration interval and ultimately, drug withdrawal. However, alteration in drug dose and schedule can compromise the efficacy of a particular treatment regimen, and contribute to suboptimal cancer treatment. [Frei, et al., Am. J. Med 69:585 (1980); Henderson et al., J. Clin. Oncol. 6:1501 (1988)]. For example, in the treatment of refractory epithelial cell ovarian cancers, Muggia et al. [J. Clin. Oncol. 15:987] utilized intravenous doses of pegylated liposomal doxorubicin, 50 mg/m.sup.2 every 3 weeks. When grade 3 or 4 PPES toxicity was encountered, the dose was reduced to 40 mg/m.sup.2. If grade 1 or 2 toxicity persisted beyond a three-week period, the administration interval was lengthened to 4 weeks. Grade 3 PPES was observed in 31% of patients (11 of 35) and required dose reductions and/or dose delay after a median of three therapy cycles.
Pyridoxine therapy has been utilized to alleviate the onset of PPES during treatment with fluorouracil infusions for metastatic colon cancer. [Fabian et al., Investigational New Drugs, 8:57 (1990)]. However, the addition of pyridoxine to the combination of altretamine plus cisplatin in state II-IV epithelial ovarian cancer patients resulted in a significant reduction in response duration (i.e., pyridoxine reduces the effectiveness of the chemotherapy treatment). [Wiernik et al., Cancer Investigation, 10:1]. Pyridoxine has been suggested for the management of pegylated liposomal doxorubicin-induced PPES in some phase II trials, but its effectiveness has not been demonstrated.
There is a need for improved methods for preventing and treating PPES that are safe and effective, and do not interfere with the effectiveness of other drugs being administered.